The synthesis of the glucuronides of ester-containing compounds is difficult to carry out by conventional synthetic chemical techniques such as the Koenigs-Knorr reaction. The difficulty of such techniques makes them impractical for the preparation of essentially pure preparations of desired glucuronides. In order to overcome this problem, enzymatic processes were invented to prepare desired glucuronide compounds.
In one such enzymatic process the O-.beta.-D-glucuronide of scopolamine, an ester-containing alkaloid, was prepared by the use of UDPGA transferase (EC 2.4.1.17) in the presence of an esterase inhibitor. In another process the O-.beta.-D-glucuronide of scopolamine was synthesized by the .beta.-glucuronidase (EC 3.2.1.31)-catalyzed reaction of scopolamine and glucuronic acid. These processes are disclosed herein.
Attempts to prepare the N-oxide of the O-.beta.-D-glucuronide of scopolamine by use of scopolamine N-oxide as the starting material in the above enzymatic processes resulted in the obtention of low yield of desired product. This low yield made it impossible to isolate sufficient quantities of desired product.
Thus, methods reasonably suggested by the prior art do not afford sufficient quantities of the N-oxide of the O-.beta.-D-glucuronide of scopolamine which can be isolated, much less essentially pure preparations of this product.
Though the O-.beta.-D-glucuronide of scopolamine is specifically disclosed herein, it is merely exemplary of the scope of glucuronide compounds which can be used to make novel N-oxides. Generically, the scope of glucuronide starting material encompasses the O-.beta.-D-glucuronides of an anticholinergic compound which contains a tertiary nitrogen. Examples of such compounds, in addition to the O-.beta.-D-glucuronides of scopolamine, are the O-.beta.-D-glucuronides of tropicamide, atropine, hyoscyamine, and the like.
The subject process for the preparation of the N-oxides of the O-.beta.-D-glucuronide of an anticholinergic compound which contains a tertiary nitrogen gives the desired compounds in their essentially pure form. This is possible because the subject process, unexpectedly, gives sufficient yield of desired product; a yield which is considerably higher than that obtainable by what the prior art might reasonably suggest as a process for making such N-oxide products. We are not aware of any prior art process which has been used specifically to make the compounds of the subject invention.